The invention relates to the treatment of depressive disorders and mania.
Stressors that cause symptoms of depression increase the activation of cAMP response element-binding protein (CREB) in the nucleus accumbens. CREB activation results in the activation of the prodynorphin gene, which encodes the opioid peptide dynorphin. Dynorphin is an agonist of the kappa opioid receptors in the brain, and enhances symptoms of depression. It has been shown that kappa receptor antagonists can act as antidepressants by mediating a disinhibition of dopamine release in the nucleus accumbens. See Pliakas et al., J. Neurosci. 21:7397 (2001); and Mague et al., J. Pharmacol. Exp. Ther. 305:323 (2003). It has been shown that antimanic/antipsychotic drugs increase the activity of dynorphinergic neurons, which have their effects through kappa receptors (Ma et al., Neuroscience 121:991 (2003).
The diterpene salvinorin A, derived from Salvia divinorum, has recently been shown to be a high affinity and selective kappa opioid receptor agonist. See Roth et al., Proc. Natl. Acad. Sci. USA 99:11934 (2002); and Butelman et al., Psychopharmacology 172:220 (2004).
New compounds which are highly selective for kappa opioid receptors over mu and delta opioid receptors and which have kappa antagonist, kappa partial agonist, or kappa agonist activity are needed to provide improved methods for the treatment of affective disorders and other conditions for which kappa opioid receptor signaling plays a role in the pathogenesis of disease.